A few human and animal syndromes resulting from decreased production of mitochondrial ATP have been described. The symptoms expected and found included elevated BMR, muscle weakness, myocardiopathy and low body weight. An unexpected consequence in a rabbit was achondroplasia. We propose to isolate an oxidative phosphorylation mutant of a metazoan and document the physiologic and metabolic correlates of decreased ATP. The initial model would be devised with a free-living nematode, Caenorabditis elegans. Similar phenotypes will be selected for study from available mouse mutants and finally, in the distant future, human biopsy material will be examined. The mutants will be produced with chemical mutagens, selected on the basis of slow movement, growth and reproduction, elevated body temperature and sensitivity to uncouplers and inhibitors of oxidative phosphorylation. Mitochondria isolated from the mutants will be characterized for oxidative activities and activities in energy-linked reactions. Microscopic and electron microscope observations of the nematode as well as ultra-structural studies on their mitochondria will be carried out to characterize abnormalities. The activities of overall metabolic reactions which utilize ATP will be determined to localize the most sensitive targets.